Role of Fibroblasts in Cancer

描述(申请人提供)：肿瘤是已知的无法愈合的伤口--意味着参与血管生成和损伤反应的细胞，如内皮细胞和成纤维细胞，在癌症的进展、生长和扩散中具有突出的作用。我们对静息和激活的成纤维细胞(也称为肿瘤相关成纤维细胞，CAF)在癌症中的作用的了解仍在发展中。成纤维细胞产生的生长因子、趋化因子和细胞外基质可能促进内皮细胞和周细胞的血管生成募集。此外，成纤维细胞在肿瘤的募集和转移形成中的确切作用完全未知。因此，这项拨款申请的重点是成纤维细胞在癌症进展中的作用，并特别强调转移。来自其他实验室的新数据和我们自己的初步数据表明，成纤维细胞是一个异质性群体。在肿瘤微环境中，我们现在已经鉴定出一组CAF对成纤维细胞特异性蛋白1(FSP1)呈阳性，但对α-平滑肌肌动蛋白(ASMA)不呈阳性。我们的研究首次证明，并不是所有的CAF都是ASMA+。此外，利用携带FSP1启动子驱动的胸苷激酶蛋白(FSP1-tk)的转基因小鼠对FSP1+/alphaSMA-成纤维细胞进行特异性消融，表明FSP1+成纤维细胞在转移的形成中起关键作用，而对血管生成原发肿瘤的生长没有显著影响。此外，我们还证明了血管内皮生长因子、SDF-1和Tenascin-C可能参与了转移结节的形成。为了进一步评估这些成纤维细胞在转移形成中的作用，我们提出了以下目标：1.评价FSP1+成纤维细胞在原发肿瘤生长和转移中的作用；2.探讨FSP1+成纤维细胞产生的血管内皮生长因子在原发肿瘤生长和转移形成中的作用；3.研究FSP1+成纤维细胞产生的SDF-1在转移形成中的作用；4.研究FSP1+成纤维细胞产生的细胞外基质蛋白Tenascin-C在转移结节组织中的作用。这项拨款申请中提出的实验的成功完成将为FSP1+成纤维细胞作为转移组织的关键决定因素的作用提供重要的见解。公共HeARLTH相关性：癌细胞不是原发肿瘤和继发转移的唯一构成细胞。在原发肿瘤和继发转移结节内可发现包括成纤维细胞在内的其他细胞。这种成纤维细胞在癌症进展和转移中的作用尚不清楚。这项建议阐述了成纤维细胞在促进转移中的作用。

DESCRIPTION (provided by applicant): Tumors are known as wounds that do not heal - implying that cells involved in angiogenesis and injury response, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Our knowledge regarding the role of the resting and the activated fibroblasts (also known as carcinoma-associated fibroblasts, CAF) in cancer is still evolving. Fibroblast production of growth factors, chemokines and extracellular matrix likely facilitates the angiogenic recruitment of endothelial cells and pericytes. Moreover, the precise role of fibroblasts in the recruitment and the formation of metastasis is completely unknown. Therefore, this grant application is focused on the role of fibroblast in cancer progression, with specific emphasis on metastasis. Emerging data from other laboratories and our own preliminary data suggest that fibroblasts are a heterogeneous population. In the tumor microenvironment, we have now identified a population of CAF that are positive for fibroblast specific protein-1 (FSP1) but not for alpha-smooth muscle actin (aSMA). Our studies demonstrate for the first time that not all CAF are aSMA+. Additionally, specific ablation of FSP1+/alphaSMA- fibroblasts using transgenic mice, which harbor FSP1 promoter driven thymidine kinase protein (FSP1-tk), demonstrate that FSP1+ fibroblasts are critical for the formation of metastasis without a significant impact on the growth of angiogenic primary tumors. Furthermore, we demonstrate that VEGF, SDF-1 and Tenascin-C, might mediate the formation of metastatic nodules. To further evaluate the role of these fibroblasts in the formation of metastasis, we propose the following aims in this proposal: 1. To evaluate the contribution of FSP1+ fibroblasts in the growth of primary tumors and recruitment of metastasis, 2. To address the contribution of VEGF produced by FSP1+ fibroblasts in the growth of primary tumors and the formation of metastasis, 3. To investigate the contribution of SDF-1, produced by FSP1+ fibroblasts, a downstream effector of VEGF, in the formation of metastasis, and 4. To study the contribution of Tenascin-C, a FSP1+ fibroblast-produced extracellular matrix protein, in the organization of metastasis nodules. Successful completion of experiments proposed in this grant application will provide crucial insights into the role of FSP1+ fibroblasts as key determinants for the organization of metastasis. PUBLIC HEARLTH RELEVANCE: Cancer cells are not the only constituent cells within a primary tumor and secondary metastasis. Other cells including fibroblasts are found inside the primary tumor and secondary metastatic nodules. The role of such fibroblasts in cancer progression and metastasis is unknown. This proposal addresses the role of fibroblasts in facilitating metastasis.